Mutations of the Anti-Müllerian Hormone Gene in Patients with Persistent Müllerian Duct Syndrome: Biosynthesis, Secretion, and Processing of the Abnormal Proteins and Analysis Using a Three-Dimensional Model

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 18; no. 3; pp. 708 - 721
• Main Authors: Belville, Corinne, Van Vlijmen, Herman, Ehrenfels, Christian, Pepinsky, Blake, Rezaie, Alireza R., Picard, Jean-Yves, Josso, Nathalie, Clemente, Nathalie di, Cate, Richard L.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-03-2004; Endocrine Society
• Subjects: Amino Acid Sequence; Animals; Anti-Mullerian Hormone; Biochemistry; Biochemistry, Molecular Biology; COS Cells; Cricetinae; Cysteine - genetics; Disorders of Sex Development - genetics; Glycoproteins - chemistry; Glycoproteins - genetics; Glycoproteins - metabolism; Glycoproteins - secretion; Glycosylation; Humans; Life Sciences; Models, Molecular; Molecular biology; Molecular Sequence Data; Mutation; Protein Conformation; Protein Folding; Protein Processing, Post-Translational; Protein Structure, Tertiary; Reproductive Biology; Sexual reproduction; Testicular Hormones - chemistry; Testicular Hormones - genetics; Testicular Hormones - metabolism; Testicular Hormones - secretion
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2003-0358

Abstract
Anti-Müllerian hormone (AMH), a TGF-β family member, determines whether an individual develops a uterus and Fallopian tubes. Mutations in the AMH gene lead to persistent Müllerian duct syndrome in males. The wild-type human AMH protein is synthesized as a disulfide-linked dimer of two identical 70-kDa polypeptides, which undergoes proteolytic processing to generate a 110-kDa N-terminal dimer and a bioactive 25-kDa TGF-β-like C-terminal dimer. We have studied the biosynthesis and secretion of wild-type AMH and of seven persistent Müllerian duct syndrome proteins, containing mutations in either the N- or C-terminal domain. Mutant proteins lacking the C-terminal domain are secreted more rapidly than full-length AMH, whereas single amino acid changes in both domains can have profound effects on protein stability and folding. The addition of a cysteine in an N-terminal domain mutant, R194C, prevents proper folding, whereas the elimination of the cysteine involved in forming the interchain disulfide bond, in a C-terminal domain mutant, C525Y, leads to a truncation at the C terminus. A molecular model of the AMH C-terminal domain provides insights into how some mutations could affect biosynthesis and function.